Stroke and Risk of Epilepsy: A Danish Nationwide Register-Based Study.

BACKGROUND: Stroke is associated with a risk of epilepsy, but associations with age, sex, stroke type and severity, time trends, and mortality are uncertain. We studied the risk of epilepsy after stroke while accounting for sex, age, stroke types and severity, calendar time, and death. METHODS: This was a prospective nationwide register-based, matched cohort study of patients admitted with a validated first stroke in Denmark from April 1, 2004, to December 16, 2018, excluding those with prior epilepsy. Patients with stroke were matched 10:1 on age, sex, and calendar time with reference people without prior epilepsy or stroke. We estimated the cumulative incidence of an epilepsy diagnosis in the Danish National Patient Registry (International Classification of Diseases Tenth Revision: G40) with death as a competing risk using competing risk regression and estimated adjusted hazard ratios by Cox regression models. RESULTS: We identified 101 034 patients with stroke (46.5% female; mean age, 70.4 years) who survived 14 days after stroke along with 1 010 333 matched reference people. Two years after the stroke, the cumulative incidence of epilepsy was 3.0% (95% CI, 2.9-3.2) after ischemic stroke and 8.6% (95% CI, 8.0-9.2) after intracerebral hemorrhage versus 0.7% (95% CI, 0.7-0.7) in the matched references. Compared with the reference population, the 2-year hazard ratio of epilepsy was 21.7 (95% CI, 20.3-23.2) after ischemic stroke and 61.3 (95% CI, 51.1-73.4) after intracerebral hemorrhage. The risk of epilepsy increased with stroke severity; the 2-year cumulative incidence of epilepsy was 10.5% (95% CI, 9.5-11.4) for very severe ischemic stroke and 13.1% (95% CI, 11.1-15.1) after very severe intracerebral hemorrhage. CONCLUSIONS: In this population-based study of patients with validated stroke, the absolute and relative risk estimates of poststroke epilepsy were lower compared with previous studies. Reasons for the lower risk estimates include accounting for the high mortality associated with stroke, which had a significant impact on risk especially for severe stroke.

Effect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST Trial.

BACKGROUND: Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that has proved to be safe and feasible in numerous smaller clinical trials. Mixed results have been found in recent large randomized controlled trials. This is a post hoc subgroup analysis of the RESIST trial (Remote Ischemic Conditioning in Patients With Acute Stroke), investigating the effect of RIC in different acute ischemic stroke etiologies, and whether an effect was modified by treatment adherence. METHODS: Eligible patients were adults (aged ≥18 years), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 hours. They were randomized to RIC or sham. The RIC treatment protocol consisted of 5 cycles with 5 minutes of cuff inflation alternating with 5 minutes with a deflated cuff. Acceptable treatment adherence was defined as when at least 80% of planned RIC cycles were received. The analysis was performed using the entire range (shift analysis) of the modified Rankin Scale (ordinal logistic regression). RESULTS: A total of 698 had acute ischemic stroke, 253 (36%) were women, and the median (interquartile range) age was 73 (63-80) years. Median (interquartile range) overall adherence to RIC/sham was 91% (68%-100%). In patients with a stroke due to cerebral small vessel disease, who were adherent to treatment, RIC was associated with improved functional outcome, and the odds ratio for a shift to a lower score on the modified Rankin Scale was 2.54 (1.03-6.25); P=0.042. The association remained significant after adjusting for potential confounders. No significant associations were found with other stroke etiologies, and the overall test for interaction was not statistically significant (χ2, 4.33, P=0.23). CONCLUSIONS: In patients with acute ischemic stroke due to cerebral small vessel disease, who maintained good treatment adherence, RIC was associated with improved functional outcomes at 90 days. These results should only serve as a hypothesis-generating for future trials. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777.

Type 2 diabetes mellitus in patients with ischemic stroke - A nationwide study.

AIMS: Type 2 diabetes (T2D) is a risk factor for ischemic stroke (IS) and associated with an adverse prognosis. Both stroke and diabetes care has evolved substantially during the last decade. This study aimed to determine the prevalence of T2D among IS patients along with time trends in the risk profile, use of glucose-lowering medications, quality-of-care and clinical outcomes, including stroke severity; length-of-stay; mortality, readmission and recurrent stroke in a large national cohort. METHODS: Registry-based cohort study including all IS events in Denmark from 2004 to 2020. IS with co-morbid T2D were compared to IS without diabetes while adjusting for age, sex, stroke severity, co-morbidity and socio-economic factors. RESULTS: The study included 169,262 IS events; 24,479 with co-morbid T2D. The prevalence of T2D in IS increased from 12.0% (2004-2006) to 17.0% (2019-2020). The adjusted absolute 30-day mortality risk in IS with T2D decreased from 9.9% (2004-2006) to 7.8% (2019-2020). The corresponding adjusted risk ratios (aRR) were 1.22 95% confidence interval (1.09-1.37) and 1.29 (1.11-1.50), respectively. The aRR of 365-day mortality was in 2004-2006: 1.20 (1.12-1.29) and in 2019-2020: 1.34 (1.22-1.47). The 30- and 365-day readmissions rates were also consistently higher in IS with T2D. CONCLUSIONS: The prevalence of T2D in IS increased over time. The 30- and 365-day mortality rates decreased over the time-period but were consistently higher in IS with co-morbid T2D. Readmissions were also higher in IS with T2D. This highlights an urgent need for strategies to further improve the prognosis in IS patients with co-morbid T2D.

Glucagonlike peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors in ischemic strokes with diabetes 2.

BACKGROUND AND PURPOSE: Cardiovascular outcome trials demonstrate that glucagonlike peptide-1 receptor agonists (GLP-1RAs) reduce the risk of major adverse cardiovascular events in patients with type 2 diabetes (T2D), whereas dipeptidyl peptidase-4 inhibitors (DPP-4is) have not shown cardiovascular benefits. We compared acute ischemic stroke (AIS) with T2D treated with either a GLP-1RA or DPP-4i prior to the index stroke. METHODS: This national cohort study included AIS patients with T2D from 2017 to 2020 in Denmark who were users of a GLP-1RA or DPP-4i. To be categorized as a user, we required at least 12 months of exposure and no concurrent treatment with another newer glucose-lowering medication during the last 3 months prior to the index stroke. GLP-1RA users were compared to users of DPP-4i while adjusting for the calendar year of index stroke, age, sex, comorbidity, and socioeconomic factors. RESULTS: The study included 1567 AIS events with T2D; 593 were users of GLP-1RA and 974 of DPP-4i. The absolute risk of a very severe stroke was 2.4% (95% confidence interval [CI] = 1.2-3.7) in GLP-1RA users and 6.1% (95% CI = 4.6-7.7) in DPP-4i users. The corresponding adjusted risk ratio (aRR) of GLP-1RA versus DPP-4i was 0.49 (95% CI = 0.24-1.00). The aRRs of 30-day and 365-day mortality were 0.55 (95% CI = 0.32-0.94) and 0.72 (95% CI = 0.53-0.98), respectively. CONCLUSIONS: The risk of a very severe stroke as well as the 30-day and 365-day poststroke mortality rates were lower among the AIS patients with comorbid T2D receiving GLP-1RA prior to the index stroke compared to those receiving DPP-4i. Hence, GLP-1RA may improve stroke outcomes in comparison with DPP-4i.

Exploring vascular contributions to cognitive impairment and dementia (ENIGMA): protocol for a prospective observational study.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is common. However, the underlying pathophysiology remains largely unknown. Understanding the role of microvascular changes and finding markers that can predict PSCI, could be a first step towards better screening and management of PSCI. Capillary dysfunction is a pathological feature of cerebral small vessel disease and may play a role in the mechanisms underlying PSCI. Extracellular vesicles (EVs) are secreted from cells and may act as disease biomarkers. We aim to investigate the role of capillary dysfunction in PSCI and the associations between EV characteristics and cognitive function one year after acute ischemic stroke (AIS) and transient ischemic attack (TIA). METHODS: The ENIGMA study is a single-centre prospective clinical observational study conducted at Aarhus University Hospital, Denmark. Consecutive patients with AIS and TIA are included and followed for one year with follow-up visits at three and 12 months. An MRI is performed at 24 h and 12 months follow-up. EV characteristics will be characterised from blood samples drawn at 24 h and three months follow-up. Cognitive function is assessed three and 12 months after AIS and TIA using the Repeatable Battery for the Assessment of Neuropsychological Status. DISCUSSION: Using novel imaging and molecular biological techniques the ENIGMA study will provide new knowledge about the vascular contributions to cognitive decline and dementia. TRIAL REGISTRATION: The study is retrospectively registered as an ongoing observational study at ClinicalTrials.gov with the identifier NCT06257823.

Socioeconomic Inequalities in Functional Outcome After Reperfusion-Treated Ischemic Stroke.

BACKGROUND: We aimed to investigate whether socioeconomic status (SES) was associated with functional outcome in patients with ischemic stroke treated with reperfusion therapy (intravenous thrombolysis and/or thrombectomy). METHODS: This nationwide cohort study included reperfusion-treated patients with ischemic stroke ≥18 years registered in the Danish Stroke Registry between 2015 and 2018. Functional outcome was determined by the modified Rankin Scale score 90 days after stroke. SES was defined by educational attainment, family income, and employment status before stroke. SES data were available from Statistics Denmark and linked on the individual level with data from the Danish Stroke Registry. Uni- and multivariable ordinal logistic regression was performed for each socioeconomic parameter individually (education, income, and employment) to estimate the common odds ratios (cORs) for lower 90-day modified Rankin Scale scores. RESULTS: A total of 5666 patients were included. Mean age was 68.7 years (95% CI, 68.3-69.0), and 38.4% were female. Low SES was associated with lower odds for achieving lower 90-day modified Rankin Scale score: Low versus high education, cOR, 0.69 (95% CI, 0.61-0.79), low versus high income, cOR, 0.59 (95% CI, 0.53-0.67), and unemployed versus employed, cOR, 0.70 (95% CI, 0.58-0.83). Inequalities were reduced after adjusting for age, sex, and immigrant status, except for unemployed versus employed patients, adjusted cOR, 0.66 (95% CI, 0.54-0.80). No statistically significant differences remained after adjusting for potentially mediating variables (eg, stroke severity, prestroke modified Rankin Scale, and smoking). CONCLUSIONS: Socioeconomic inequalities were observed in functional outcome after reperfusion treated ischemic stroke. In particular, prestroke unemployment was negatively associated with good functional outcome. A more adverse prognostic profile among patients with low SES appeared to explain the majority of these inequalities.

Transport Strategy in Patients With Suspected Acute Large Vessel Occlusion Stroke: TRIAGE-STROKE, a Randomized Clinical Trial.

BACKGROUND: When patients with acute ischemic stroke present with suspected large vessel occlusion in the catchment area of a primary stroke center (PSC), the benefit of direct transport to a comprehensive stroke center (CSC) has been suggested. Equipoise remains between transport strategies and the best transport strategy is not well established. METHODS: We conducted a national investigator-driven, multicenter, randomized, assessor-blinded clinical trial. Patients eligible for intravenous thrombolysis (IVT) who were suspected for large vessel occlusion were randomized 1:1 to admission to the nearest PSC (prioritizing IVT) or direct CSC admission (prioritizing endovascular therapy). The primary outcome was functional improvement at day 90 for all patients with acute ischemic stroke, measured as shift towards a lower score on the modified Rankin Scale score. RESULTS: From September 2018 to May 2022, we enrolled 171 patients of whom 104 had acute ischemic stroke. The trial was halted before full recruitment. Baseline characteristics were well balanced. Primary analysis of shift in modified Rankin Scale (ordinal logistic regression) revealed an odds ratio for functional improvement at day 90 of 1.42 (95% CI, 0.72-2.82, P=0.31). Onset to groin time for patients with large vessel occlusion was 35 minutes (P=0.007) shorter when patients were transported to a CSC first, whereas onset to needle (IVT) was 30 minutes (P=0.012) shorter when patients were transported to PSC first. IVT was administered in 67% of patients in the PSC group versus 78% in the CSC group and EVT was performed in 53% versus 63% of the patients, respectively. CONCLUSIONS: This trial investigated the benefit of bypassing PSC. We included only IVT-eligible patients presenting <4 hours from onset and with suspected large vessel occlusion. Lack of power prevented the results from showing effect on functional outcome for patients going directly to CSC. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03542188.

Processes of Care and Associated Factors in Patients With Stroke by Immigration Status.

BACKGROUND: Receiving evidence-based stroke care processes is associated with good clinical outcome. However, data on early stroke care among immigrants are scarce. OBJECTIVE: We investigated whether guideline-recommended acute stroke care and associated factors differ between immigrants and Danish-born residents. DESIGN: Patients admitted with ischemic and hemorrhagic stroke diagnoses (n=129,724) between 2005 and 2018 were identified from the Danish Stroke Registry. RESULTS: We included 123,928 Danish-born residents and 5796 immigrants with stroke. Compared with Danish-born residents, immigrants were less likely to be admitted to a stroke unit within 24 hours after stroke onset (81.5% vs. 83.9%, P <0.001) and had lower odds of early stroke care including dysphagia screening, physiotherapy, occupational therapy, and nutritional assessment. After adjustment for age, sex, clinical, and sociodemographic factors, immigrants had lower odds of early stroke unit admission (odds ratio [OR]: 0.97; 95% CI, 0.94-0.99), early dysphagia screening (OR: 0.96; 95% CI, 0.93-0.98), early physiotherapy (OR: 0.96; 95% CI, 0.94-0.99), and early occupational therapy (OR: 0.96; 95% CI, 0.93-0.98) than Danish-born residents. Small absolute differences in overall quality of stroke care were found when comparing immigrants and Danish-born residents. Significant factors associated with greater likelihood of stroke care included high income, high education, and cohabitation. CONCLUSIONS: Immigrants had lower chances of early stroke unit admission and received fewer individual early stroke care processes such as dysphagia screening, physiotherapy and occupational therapy than Danish-born residents. However, the absolute disparities were in general minor and largely influenced by socioeconomic status and cohabitation.

Treatment Delays and Chance of Reperfusion Therapy in Patients with Acute Stroke: A Danish Nationwide Study.

INTRODUCTION: We aimed to determine the treatment delay for ischemic stroke patients in Denmark. METHODS: A nationwide register-based study on acute ischemic stroke patients admitted through emergency medical services. Treatment delay comprised patient, prehospital, and in-hospital delay. Analyses were stratified according to length of prehospital delay (<3 vs. ≥3 h). RESULTS: A total of 5,356 ischemic stroke episodes were included. The median onset-to-door time was 187 min, and 2,405 (43%) arrived at the stroke unit within 3 h. Overall, the median patient delay was 115 min. For early arrival (n = 2,280), patient delay was 27 min compared to 437 min for late arrivals (n = 2,448). Median prehospital delay varied by 9 min between early- and late-arriving patients. Approximately 48% of the early-arriving patients compared to 9% of the late-arriving patients received i.v. thrombolysis. For thrombectomy, the numbers were 10% and 3%, respectively. This corresponded to an unadjusted relative risk (RR) of 0.18 (95% CI: 0.16-0.21) and adjusted (age, sex, cohabitation status, and stroke severity) RR of 0.20 (95% CI: 0.18-0.23) for i.v. thrombolysis when comparing patients arriving later than 3 h with patients arriving earlier. For thrombectomy, the unadjusted and adjusted RRs were 0.30 (95% CI: 0.23-0.39) and 0.40 (95% CI: 0.31-0.52), respectively. CONCLUSIONS: Patient delay remains the most important barrier for use of reperfusion therapy among acute ischemic stroke patients calling 1-1-2, whereas system delay seems independent of patient delay.

Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Disparities in Reperfusion Therapy and Time Delays Among Patients With Ischemic Stroke and a History of Mental Illness.

BACKGROUND: Comorbid mental illness may delay recognition of stroke symptoms and reduce the chance of reperfusion therapy. The aim of this study was to compare the use of reperfusion therapy and treatment delays in patients with or without a history of mental illness. METHODS: A nationwide registry-based cohort study of patients with ischemic stroke. We combined data from the Danish Stroke Registry and the Danish Quality Database for Prehospital Emergency Medical Services from 2016 to 2017 containing information on reperfusion therapy (thrombolysis or thrombectomy) and relevant time stamps. Patients were categorized according to the severity of their mental health history (how recent and severity, for example, hospital- versus primary-based care). RESULTS: A total of 19 592 admissions were included (18% had a minor, 3% had a moderate, and 3% had a history of major mental illness). Significant differences were found regarding age, comorbidity, and socioeconomic factors. Reperfusion therapy was used in 17% of patients. Patients with a history of mental illness were less likely to receive reperfusion therapy: risk ratios with 95% CI were 0.79 (0.72-0.86) for minor, 0.85 (0.72-0.99) for moderate, and 0.63 (0.51-0.77) for patients with a history major mental illness, respectively. Total prehospital delay was longer for patients with a history of major mental illness compared to patients with no history of mental illness, especially when no call had been made to the emergency medical service. The median times from symptom onset to hospital arrival was 811 minutes (197-2845) and 115 minutes (41-188), respectively. We found no differences regarding door-to-needle time, response time, on-scene time, transport time, nor in time-to-imaging among patients arriving within 4 hours from symptoms onset between patients with and without a history of mental illness. CONCLUSIONS: Almost one-quarter of patients with ischemic stroke had a history of mental illness. Regardless of severity of mental illness, these patients were less likely to receive reperfusion therapy. Longer delays from symptom onset to hospital arrival contributed to the patients' risk of not being eligible for reperfusion therapy.

Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke.

BACKGROUND: Reperfusion therapies (thrombolysis and thrombectomy) are of paramount importance for the recovery after ischemic stroke. We aimed to investigate if socioeconomic status (SES) was associated with the chance of receiving reperfusion therapy for ischemic stroke in a country with tax-funded health care. METHODS: This nationwide register-based cohort study included patients with ischemic stroke registered in the Danish Stroke Registry between 2015 and 2018. SES was determined by prestroke educational attainment, income level, and employment status. Data on SES was obtained from Statistics Denmark and linked on an individual level with data from the Danish Stroke Registry. Risk ratios (RR) for receiving reperfusion therapies were calculated using univariate and multivariable Poisson regression with robust variance. RESULTS: A total of 37 187 ischemic stroke patients were included. Low SES, as defined by education, income and employment status, was associated with lower treatment rates. The socioeconomic gradient was most pronounced according to employment status, with intravenous thrombolysis rates of 23.7% versus 15.8%, and thrombectomy rates of 5.1% versus 2.8% for employed versus unemployed patients. When the analyses were restricted to patients with timely hospital arrival, and adjusted for age, sex and immigrant status, low SES according to income and employment remained unfavorable for the likelihood of receiving intravenous thrombolysis: adjusted RR, 0.90 (95% CI, 0.86-0.95) for low versus high income, and adjusted RR, 0.77 (95% CI, 0.71-0.84) for unemployed versus employed patients. Similarly, low SES according to income and employment status remained unfavorable for the likelihood of receiving thrombectomy: adjusted RR, 0.83 (95% CI, 0.72-0.95) for low versus high income and adjusted RR, 0.68 (95% CI, 0.53-0.88) for unemployed versus employed patients. CONCLUSIONS: Socioeconomic inequalities in reperfusion treatment rates among ischemic stroke patients prevail, even in a country with tax-funded universal health care.

Atrial fibrillation after closure of patent foramen ovale in the REDUCE clinical study.

OBJECTIVES: To describe the occurrence of postprocedural atrial fibrillation (AF) among patients with cryptogenic stroke undergoing patent foramen ovale (PFO) closure in the REDUCE clinical study and analyze for potential risk factors for the development of postprocedural AF. BACKGROUND: AF is an adverse event that might potentially counterbalance the stroke prevention benefit from PFO closure. Data on AF after transcatheter PFO closure are sparse. METHODS: We evaluated data from patients having PFO closure (Gore HELEX or Gore Cardioform Septal Occluder) in the REDUCE clinical trial (n = 408) in at post hoc explorative analysis. Median follow-up was 5.0 years. RESULTS: AF occurred in 30 patients (7.4%) after PFO closure with a total of 34 AF events. Most were reported as non-serious (68%), detected within 45 days post-procedure (79%), and resolved within 2 weeks of onset (63%). One subject with AF had recurrent stroke. Postprocedural AF occurred more frequently among subjects with higher age and large device sizes. Male sex was the only independent predictor of postprocedural AF. We found no association between the type of occluder (HELEX or Gore Cardioform Septal Occluder) or PFO anatomical characteristics and post-procedural AF. CONCLUSION: In the REDUCE clinical study, postprocedural atrial fibrillation was mostly early onset, transient and with no later recurrence. Postprocedural AF occurred more frequently among patients with higher age and larger devices. Male sex was the only independent predictor of postprocedural AF.

Use of reperfusion therapy and time delay in patients with ischaemic stroke by immigration status: A register-based cohort study in Denmark.

BACKGROUND AND PURPOSE: Reperfusion therapy is the mainstay of treatment for acute ischaemic stroke (AIS); however, little is known about the use of reperfusion therapy and time delay amongst immigrants. METHODS: This is a Danish nationwide register-based cohort study of patients with AIS aged ≥18 years (n = 49,817) recruited from 2009 to 2018. Use of reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy) and time delay between immigrants and Danish-born residents were compared using multivariable logistics and quantile regression. RESULTS: Overall, 10,649 (39.8%) Danish-born residents and 452 (39.0%) immigrants with AIS were treated with reperfusion therapy in patients arriving <4.5 h following stroke onset. Compared with Danish-born residents, immigrants had lower odds of receiving reperfusion therapy after adjustment for prehospital delay, age, sex, stroke severity, sociodemographic factors and comorbidities (adjusted odds ratio 0.67; 95% confidence interval 0.49-0.92, p = 0.01). The lowest odds were observed amongst immigrants originating from Poland and non-Western countries. Similarly, immigrants had a longer prehospital delay than Danish-born residents in the fully adjusted model in patients arriving <4.5 h after stroke onset (15 min; 95% confidence interval 4-26 min, p = 0.03). No evidence was found that system delay and clinical outcome differed between immigrants and Danish-born residents in patients eligible for reperfusion therapy after adjustment for sociodemographic factors and comorbidities. CONCLUSION: Immigration status was significantly associated with lower chances of receiving reperfusion therapy and there may be differences in patient delay between immigrants and Danish-born residents in patients arriving to a stroke unit <4.5 h after stroke onset.

Trends in the incidence and mortality of intracerebral hemorrhage, and the associated risk factors, in Denmark from 2004 to 2017.

BACKGROUND AND PURPOSE: The distribution of the major modifiable risk factors for intracerebral hemorrhage (ICH) changes rapidly. These changes call for contemporary data from large-scale population-based studies. The aim of the present study was to examine trends in incidence, risk factors, and mortality in ICH patients from 2004 to 2017. METHODS: In a population-based cohort study, we calculated age- and sex-standardized incidence rates (SIRs), incidence rates (IRs) stratified by age and sex per 100,000 person-years, and trends in risk profiles. We estimated absolute mortality risk, and the Cox proportional hazards regression multivariable-adjusted hazard ratios for 30-day and 1-year mortality. RESULTS: We included 16,902 patients (53% men; median age 75 years) from 2004 to 2017. The SIR of ICH decreased from 33 (95% confidence interval [CI] 32-34) in 2004/2005 to 28 (95% CI 27-29) in 2016/2017. Among patients aged ≥70 years, the IR decreased from 137 (95% CI 130-144) in 2004/2005 to 112 (95% CI 106-117) in 2016/2017. The IR in patients aged <70 years was unchanged. From 2004 to 2017, the proportion of patients with hypertension increased from 49% to 66%, the use of oral anticoagulants increased from 7% to 18%, and the use of platelet inhibitors decreased from 40% to 28%. The adjusted hazard ratio for 30-day mortality in 2016/2017 was 0.94 (95% CI 0.89-1.01) and 1-year mortality was 0.98 (95% CI 0.93-1.04) compared with 2004/2005. CONCLUSION: The incidence of spontaneous ICH decreased from 2004 to 2017, with no clear trend in mortality. The risk profile of ICH patients changed substantially, with increasing proportions of hypertension and anticoagulant treatment. Given the high mortality rate of ICH, further advances in prevention and treatment are urgently needed.

COVID-19 did not result in increased hospitalization for stroke and transient ischemic attack: A nationwide study.

BACKGROUND: The risk of thrombosis increases in infectious diseases, yet observational studies from single centers have shown a decrease in admission of acute ischemic stroke patients during the COVID-19 pandemic. To investigate unselected stroke admission rates we performed a nationwide study in Denmark. METHODS: We extracted information from Danish national health registries. The following mutually exclusive time periods were compared to the year before the lockdown: (1) first national lockdown, (2) gradual reopening, (3) few restrictions, (4) regional lockdown, and (5) second national lockdown. RESULTS: Generally, admission rates were unchanged during the pandemic. In the unadjusted data, we observed a small decrease in the admission rate for all strokes under the first lockdown (incidence rate ratio: 0.93, confidence interval [CI]: 0.87-0.99) and a slight increase during the periods with gradual reopening, few restrictions, and the regional lockdown driven by ischemic strokes. We found no change in the rate of severe strokes, mild strokes, or 30-day mortality. An exception was the higher mortality for all strokes during the first lockdown (risk ratio: crude 1.30 [CI: 1.03-1.59]; adjusted 1.17 [CI: 0.93-1.47]). The quality of care remained unchanged. CONCLUSION: Stroke admission rates remained largely unchanged during the pandemic, while an increased short-term mortality rate in patients admitted with stroke observed during the first lockdown was seen, probably reflecting that the more frail patients constituted a higher proportion of admitted patients at the beginning of the pandemic.

The impact of a Danish stroke campaign: A cross-sectional study.

OBJECTIVES: To investigate the impact of the Danish stroke campaign, 1 year after initiation. MATERIALS & METHODS: The campaign ran in various media during 2019-2020. We performed a two-centre, repeated cross-sectional study in 2018 (before campaign) and again in 2020 based on data from structured interviews of patients and bystanders, medical records and the Danish Stroke Registry. Primary outcomes were patient delay and system delay. Patient delay is defined as the time from symptom onset until the first contact to a healthcare professional, whereas system delay is the time from this contact until arrival at the stroke centre. Secondary outcomes were primary emergency medical services (EMS) contact, arrival at a stroke centre within 3 h of symptom onset, initiation of reperfusion therapy and knowledge of ≥2 core symptoms of stroke. RESULTS: We included 852 patients with stroke or transient ischemic attack. Patient delay and system delay were a median of 166 min and 96 min before the campaign and were non-significantly reduced by 16 min (95% CI -128 to 97) and 7 min (95% CI -21 to 6) in the second period. We found no significant differences in the clinical outcomes. The knowledge of ≥2 core symptoms increased from 22% to 30% (OR 1.63; 95% CI 1.15 to 2.30) in patients and from 53% to 65% (OR 1.81; 95% CI 1.24 to 2.64) in bystanders. CONCLUSION: Patient delay, system delay and clinical outcomes remained relatively unchanged. However, the knowledge of core symptoms had improved 1 year after campaign initiation.

The Prehospital Stroke Score and telephone conference: A prospective validation.

OBJECTIVES: The main aim of the study is to investigate the performance of a two-part stroke scale for screening and subsequent severity assessment combined with a telephone conference (teleconference). MATERIALS AND METHODS: During a 6-month period, we prospectively tested the Prehospital Stroke Score (PreSS). PreSS part 1 is designed to identify stroke or TIA in a prehospital setting. PreSS part 2 is a stroke severity scale designed to identify large-vessel occlusion (LVO). PreSS was performed by emergency medical service (EMS) providers prior to a teleconference with a stroke neurologist. RESULTS: Combined teleconference and PreSS part 1 were performed on 79.3% of all patients diagnosed with stroke/TIA, and 99.1% of the patients with positive scores were subsequently PreSS part 2 scored. PreSS part 1 and teleconference had a sensitivity to identify stroke/TIA of 89.3% (95% CI 85.7-92.2), specificity of 64.5% (95% CI 59.3-69.5), and an area under the curve (AUC) of 0.80 (95% CI 0.77-0.83). Regarding LVO, PreSS part 1 with teleconference recognized 96.7% (95% CI 88.7-99.6) of all cases as stroke. PreSS part 2 had a sensitivity of 55.7% (95% CI 42.4-68.5), specificity of 91.5% (95% CI 89.0-93.6), and AUC of 0.86 (95% CI 0.82-0.90) for identification of LVO. CONCLUSIONS: PreSS was feasible and the sensitivity for stroke/TIA and LVO was high to moderate providing an overall high precision. Almost all LVO cases were ensured acute stroke admission. The high specificity for LVO could be useful for determining transfers strategies. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence when evaluating PreSS combined with teleconference.

Patent Foramen Ovale Closure Decreases the Incidence but Not the Size of New Brain Infarction on Magnetic Resonance Imaging: An Analysis of the REDUCE Trial.

Background and Purpose: Randomized patent foramen ovale closure trials have used open-label end point ascertainment which increases the risk of bias and undermines confidence in the conclusions. The Gore REDUCE trial prospectively performed baseline and follow-up magnetic resonance imaging (MRIs) for all subjects providing an objective measure of the effectiveness of closure. Methods: We performed blinded evaluations of the presence, location, and volume of new infarct on diffusion-weighted imaging of recurrent clinical stroke or new infarct (>3 mm) on T2/fluid attenuated inversion recovery from baseline to follow-up MRI at 2 years, comparing closure to medical therapy alone. We also examined the effect of shunt size and the development of atrial fibrillation on infarct burden at follow-up. Results: At follow-up, new clinical stroke or silent MRI infarct occurred in 18/383 (4.7%) patients who underwent closure and 19/177 (10.7%) medication-only patients (relative risk, 0.44 [95% CI, 0.24­0.81], P=0.02). Clinical strokes were less common in closure patients compared with medically treated patients, 5 (1.3%) versus 12 (6.8%), P=0.001, while silent MRI infarcts were similar, 13 (3.4%) versus 7 (4.0%), P=0.81. There were no differences in number, volumes, and distribution of new infarct comparing closure patients to those treated with medication alone. There were also no differences of number, volumes, and distribution comparing silent infarcts to clinical strokes. Infarct burden was also similar for patients who developed atrial fibrillation and for those with large shunts. Conclusions: The REDUCE trial demonstrates that patent foramen ovale closure prevents recurrent brain infarction based on the objective outcome of new infarcts on MRI. Only clinical strokes were reduced by closure while silent infarctions were similar between study arms, and there were no differences in infarct volume or location comparing silent infarcts to clinical strokes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00738894.

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).